tbuckley/cabot-search huggingface dataset:
Abstract 6393: The Cancer Genomics Cloud enables bioinformatics training in a hybrid educational world
Authors: Manisha Ray, Sai Lakshmi Subramanian, David Roberson, Zelia Worman, Dennis A. Dean, Soner Koc, Jack DiGiovanna, Brandi Davis-Dusenbery
Journal: Cancer Research (2022)

Abstract The Cancer Genomics Cloud (CGC), powered by Seven Bridges, is an NCI-funded platform that streamlines access to large cancer datasets, bioinformatic tools, and cloud computation for cancer researchers. The attributes of the CGC designed to democratize data analysis also make it ideal for training the next generation of data scientists. During the Covid-19 pandemic, it has become clear that remote/virtual learning is of great importance for workforce development, and that reducing barriers to high quality educational resources is critical for many populations. Here we present our best practices for education of bioinformatics using the CGC, taking advantage of both distributed cloud networks and platform features to enhance learning. Our best practices methods are focused on a systematic approach that takes the instructor and students through a typical bioinformatics workflow in their field of research. Briefly, the organizational structure of the CGC, known as “projects,'' contains all aspects of an analysis, including data files, tools, and tool settings. Projects have fine-grained permission settings, which allow the owner to securely share their project for viewing or editing. An instructor can generate an example analysis from start to finish then share an entire project with trainees. Both students and instructors have access to the same data on the cloud, so the teacher can pre-populate the projects with specific files, ensuring the same starting point. All members within the project can communicate, including adding notes directly on the results, allowing students to troubleshoot in real time with the teacher. Instructors can manage costs for the whole class through the CGC’s billing system. The CGC also provides Public Projects for self-guided training, where a researcher can learn by example using the data, tools, and completed tasks within the project, including detailed instructions embedded in markdown language. We have successfully used these methods to train masters students in bioinformatics at Georgetown University for three years, as well as high school students, college students, and current cancer researchers. This approach to virtual learning of bioinformatics can democratize training for the next generation of data scientists. The FAIR practices built into the CGC enables education across all levels of expertise, empowering users to drive cancer research from any stage of their career. Citation Format: Manisha Ray, Sai Lakshmi Subramanian, David Roberson, Zelia Worman, Dennis A. Dean, Soner Koc, Jack DiGiovanna, Brandi Davis-Dusenbery. The Cancer Genomics Cloud enables bioinformatics training in a hybrid educational world [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6393.
Association of Sex, Reduced Myocardial Flow Reserve, and Long-Term Mortality Across Spectrum of Atherosclerotic Disease
Authors: Krishna K. Patel, Leslee Shaw, John A. Spertus, Brett Sperry, A. Iain McGhie, Kevin Kennedy, Randall C. Thompson, Paul S. Chan, Timothy M. Bateman
Journal: JACC. Cardiovascular imaging (2022)
Abstract 3731: Epigenetic control of tumor cell killing by natural killer cells
Authors: Joyce Pasion, Darko Barisic, Cem Meydan, Kong Y. Ng, Maria Tello Lafoz, Morgan Huse, Ari Melnick, Hans-Guido Wendel
Journal: Cancer Research (2022)

Abstract Immunotherapies including the activation of endogenous immune cells have stimulated great interest for their anti-tumor functions. An initial focus has been on genetic lesions such as loss of MHC class I and class II molecules that facilitate tumor cell escape. More recently, epigenetic mechanisms such as the disruption of the SWI/SNF remodeling complex PBAF have been implicated in regulating tumor sensitivity to CD8 T cell-mediated killing. Here, I used an unbiased genetic screening approach to examine resistance and sensitivity of breast cancer cells to Natural Killer (NK) cells. Among expected hits including caspases, interferon receptors, and cell death executioners, the screen revealed a surprising role of alternate SWI/SNF complexes in controlling NK cell-mediated cytotoxicity that relate to interferon-γ and perforin/granzyme B, and may be pharmacologically reversible. Altogether, I will discuss a new epigenetic mechanism that affect NK cell-mediated cytotoxicity with a focus on SWI/SNF complexes. Citation Format: Joyce Pasion, Darko Barisic, Cem Meydan, Kong Y. Ng, Maria Tello Lafoz, Morgan Huse, Ari Melnick, Hans-Guido Wendel. Epigenetic control of tumor cell killing by natural killer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3731.
Abstract 991: OVO-like genes are master regulators of the epithelial fate in breast cancer
Authors: Diana Drago Garcia, Yosef Yarden
Journal: Cancer Research (2022)

Abstract The OVO-like genes are evolutionary conserved C2H2 zinc finger transcription factors (TFs) with SNAG repressor domains involved in the maintenance of epithelial homeostasis. From the three Ovo-like family genes identified in mammals, Ovol-like1 (Ovol1) and Ovol-like2 (Ovol2) are the most studied members with multiple reports pinpointing relevant roles in development and disease. In cancer, one of the hallmarks of invasive carcinoma involves the loss of E-cadherin expression by the repression of SNAG transcription factors. Interestingly, contrary to the other SNAG domain family members the OVO-like genes regulate epithelial cell fate. We performed data analysis in breast cancer cell lines and patient data obtained from GEO, CCLE, TCGA and METABRIC to assess the potential of the OVO-like genes as relevant regulators of gene expression in breast carcinoma. In addition, we stablished breast cancer models with inducible expression or repression of the OVO-like genes. We also analyzed the cellular systems we generated using naïve high-throughput methods such as RNA-Seq. Likewise, we studied the effect of OVO-like genes on tumor progression and metastasis using inducible expression systems in both xenograft and syngeneic breast cancer models. We observed that Ovol1 and Ovol2 are constitutively expressed in human breast cancer cell lines, and they are upregulated due to chromosomal gains in breast cancer patients. We observed how the introduction of Ovol1 and Ovol2 into mesenchymal-like breast cancer cell lines modified their transcriptome in a way that promoted expression of epithelial marker genes (e.g., Amphiregulin) and downregulated mesenchymal markers (e.g., Vimentin). In addition, introducing Ovo-like genes in mesenchymal-like cells greatly affected their viability and function. Surprisingly, we observed a similar effect by downregulating the Ovo-like genes in epithelial-like cells. We propose a model where a common epigenetic machinery is shared between structurally related transcription factors with opposing effects, such as OVO-like proteins and other SNAG-containing transcription factors, such as Snail and Slug, such that the abundance of the transcription factors and their co-repressors defines the state of the system as either epithelial or mesenchymal. Citation Format: Diana Drago Garcia, Yosef Yarden. OVO-like genes are master regulators of the epithelial fate in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 991.
Abstract 1485: Identification and <i>in vitro</i> validation of miRNA biomarker candidates in head and neck squamous cell carcinoma using a network biology approach
Authors: Laiba Shah, Maryam Shah, Abdus Salam, Khudeja Salim, Faisal F. Khan
Journal: Cancer Research (2022)

Abstract Micro-RNAs are small non-coding RNAs that are able to modulate the gene expression. Aberrant expression of micro-RNAs leads to different diseased conditions such as cancer. Head and Neck Squamous Cell Carcinoma (HNSCC) is the second most prevalent cancer in Pakistan and contributes to 9.1% of mortality annually due to late stage diagnosis and ineffective treatment. This research attempts to identify novel miRNAs candidates for their potential role as diagnostic, prognostics or therapeutic biomarkers in HNSCC patient-derived primary cells in the Pakistani population. miRNA species and their gene targets reported in HNSCC were identified using the miRbase, miRNet, and miRCancer databases, and a total of 69 miRNAs with differential expression levels in HNSCC were selected to seed a miRNA-Gene interaction network that was created using BioGrid and STRING data. Hub genes that were targeted by over-expressed miRNAs were predicted using miRTarbase. GO and KEGG analysis was carried out for the 181 interacting genes including TP53, SMAD4, PTEN, NOTCH2, and STAT3. Enrichment analysis demonstrated the increased involvement of these miRNAs in Cancer Pathways such as Hippo signaling Pathways and FoxO signaling pathways. We prioritized hub genes that were targeted by the highest number of tumor suppressor genes, and identified five miRNA species, including miR-21-5p, miR-16-5p, miR30a-5p, miR-93-5p, and miR106b-5p, as the best biomarker candidates for experimental validation. To validate the in silico findings, the top five microRNA candidates are being screened for expression in a library of local patient-derived primary cell lines from Pakistani HNSCC patients. Citation Format: Laiba Shah, Maryam Shah, Abdus Salam, Khudeja Salim, Faisal F. Khan. Identification and in vitro validation of miRNA biomarker candidates in head and neck squamous cell carcinoma using a network biology approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1485.
Abstract 4081: Leveraging single-cell RNA sequencing data to design multi-targeting SeekRRNA therapeutics
Authors: Susan Massey, Richard Hsiao, Shweta Yadav, David Azorsa, Spyro Mousses, Jeffrey A. Kiefer
Journal: Cancer Research (2022)

Abstract SeekR™ chimeric molecules consist of dual flanking RNA aptamers designed to bind specific proteins (BINDERS), joined by a double stranded RNA bridge that encodes multiple siRNAs designed to silence select disease target genes (SILENCERS). Aptamers are folded nucleic acid chains that act much like chemical antibodies in that they can bind proteins in a sequence-specific manner. By identifying RNA aptamers capable of seeking and binding to specific cell surface protein receptors, SeekR™ RNA therapeutics can be engineered to self-deliver to a particular receptor defined tissue type. For example, a SeekR™ can be directed to prostate tumors that selectively express PSMA. The combination of two RNA aptamer binders with two siRNA silencers thus enables the selective delivery of the siRNAs to tumor cells expressing the binder target, wherein it directs sequence-specific silencing of cancer target genes. To identify and prioritize the right combination of SeekR targets, we have taken advantage of single-cell sequencing (scRNA-seq) data sets. By analyzing scRNA-seq data, we can identify specific cell populations within tumors to co-target with an aptamer and siRNA. We leveraged several publicly available colon and non-small cell lung cancer scRNA data sets for this analysis. A custom analysis pipeline was applied to these data to identify specific cell types within tumor samples. We then profiled specific cancer targets and determined percentages of target co-expression within a single tumor compared to normal cells. This provides information for cell-type-specific targeting to reduce potential toxicity within non-tumor tissue. In addition to targeting aptamers, we performed ligand-receptor analyses to prioritize specific siRNA targets in particular cell types within the tumor environment. This analysis revealed novel combinations of binders and silencers that will more precisely deliver the right multi-targeted gene silencing to the correct cell types. In summary, scRNA-seq data provide a rich resource of data to direct SeekR™ development and optimization. Citation Format: Susan Massey, Richard Hsiao, Shweta Yadav, David Azorsa, Spyro Mousses, Jeffrey A. Kiefer. Leveraging single-cell RNA sequencing data to design multi-targeting SeekRRNA therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4081.
Abstract 3022: Tryptophan metabolism is associated with obesity and triple negative breast cancer risk in black and white women
Authors: Alana Smith, Qingqing Gu, Ernestine Kubi Amos-Abanyie, Elizabeth Tolley, Lu Lu, Beverly Lyn-Cook, Athena Starlard-Davenport
Journal: Cancer Research (2022)

Abstract Non-Hispanic black (NHB) women are more likely to be diagnosed and die from triple negative breast cancer (TNBC) than non-Hispanic white (NHW) women. We previously showed that TNBC tissues display a distinct microbial signature. Obesity which contributes to chronic low-grade inflammation and gut microbial dysbiosis further exacerbates TNBC outcomes for NHB women. However, it is unclear the extent to which microbial differences in breast tumor tissues may be driven by alterations in microbial metabolites as a result of obesity status. Therefore, the aim of this global metabolomic profiling study was to investigate alterations in microbial metabolism pathways in breast tissues of NHB and NHW obese women (avg. BMI = 35.7) relative to non-obese women (avg. BMI = 23.4) with and without TNBC. In this study, we analyzed 984 metabolites derived from a total of 51 NHB and NHW women, including 15 patients with TNBC, 12 patients with less aggressive Luminal A-type breast cancer, and 24 healthy controls for comparison using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to identify microbial metabolites and metabolomic signatures that differ by breast tumor subtype and obesity status. We detected 501 significantly increased metabolites and 33 significantly decreased metabolites in TNBC patients compared to controls. Principal component analysis and hierarchical clustering of the global metabolite profiling data revealed separation between the metabolic signatures of normal and breast tumor tissue. Random forest analysis revealed a unique biochemical signature associated with elevated L-Tryptophan (Trp) and Kynurenine (Kyn) metabolites and lower levels of microbial-derived metabolites critical for controlling inflammation and immune response in obese individuals and those with TNBC. TCGA analysis further revealed that expression of key Trp enzymes was significantly associated with worse survival outcomes in TNBC patients compared to other breast tumor subtypes. Our findings highlight a potential role for Trp metabolism through the Kyn pathway in obesity and TNBC risk. Further investigations into the Kyn metabolomic pathway may prove to be a novel therapeutic target for TNBC. Citation Format: Alana Smith, Qingqing Gu, Ernestine Kubi Amos-Abanyie, Elizabeth Tolley, Lu Lu, Beverly Lyn-Cook, Athena Starlard-Davenport. Tryptophan metabolism is associated with obesity and triple negative breast cancer risk in black and white women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3022.
Abstract 4072: Cytotoxic effects of LRRK2 inhibitors in combined treatment with chemotherapeutic agents on a large panel of cancer cell lines
Authors: Franziska Fimm-Todt, Joachim Lauterwasser, Eva-Maria Egenter, Christian Weber, Daniel Feger, Katharina Schaich, Sarah Ulrich, Oliver Siedentopf, Frank Totzke, Michael Kubbutat, Jan Erik Ehlert
Journal: Cancer Research (2022)

Abstract Leucin-rich repeat kinase 2 (LRRK2) plays an important role in the onset of sporadic as well as familial Parkinson’s disease. Pathogenic gain-of-function mutations of LRRK2 are associated with aberrant LRRK2 hyperactivity which results in neurotoxicity and protein aggregation caused by dysfunctional autophagy and vesicle trafficking. Thus, the development of LRRK2 inhibitors represents a promising strategy for the treatment of Parkinson’s disease. Interestingly LRRK2 mutations have also been reported to increase the risk for the onset of different types of cancer (e.g. breast, thyroid, lung). Several studies suggest that LRRK2 is involved in the regulation of different cancer-related pathways (e.g. ATM-p53-p21-pathway, JNK pathway). Deregulation of LRRK2 activity caused by mutations has been shown to interfere with these pathways thereby increasing the risk to develop certain types of cancer. Since anti-cancer treatments mostly target the same pathways, we hypothesized that LRRK2 inhibitors may affect anti-cancer treatments in specific cancer cell types. In this study we report on the analyses of various inhibitors (e.g. MLi-2 and PF-06447475) on LRRK2 autophosphorylation at S935 in a cellular phosphorylation assay using the non-small cell lung cancer cell line A549 in comparison to biochemical LRRK2 activity assays. Furthermore, we compare the direct LRRK2 inhibitor effect on the proliferation of 140 cell lines, as well as their potential combinatorial impact on the potency of chemotherapeutic agents (e.g. Adriamycin). The observed effects can help to understand the implications of pharmaceutical LRRK2 inhibition in the treatment of both Parkinson’s disease and cancer. Citation Format: Franziska Fimm-Todt, Joachim Lauterwasser, Eva-Maria Egenter, Christian Weber, Daniel Feger, Katharina Schaich, Sarah Ulrich, Oliver Siedentopf, Frank Totzke, Michael Kubbutat, Jan Erik Ehlert. Cytotoxic effects of LRRK2 inhibitors in combined treatment with chemotherapeutic agents on a large panel of cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4072.
Abstract 5782: Sample management for enabling successful single-cell RNAseq processing
Authors: Priya J. Halvorsen, Caitlin W. Britton, Hiba Shaban, Fernando Torres, Douglas Wilson, Joseph Modarelli
Journal: Cancer Research (2022)

Abstract Background: Single cell analysis allows the profiling of biomolecules on a cell-by-cell basis, revealing insights into how cellular heterogeneity impacts biological mechanisms. Drug discovery and development have greatly benefited from the comparative, longitudinal, and causal information single cell analysis provides, transforming our ability to understand disease. Many preclinical and clinical studies leveraging single cell resolution have already played a crucial role in target identification and biomarker discovery. From collection through analysis, proper sample management is a crucial and challenging aspect of large-scale clinical research studies and directly influences specimen quality and the ability to interrogate specific cell populations of interest. Methods: We sought to determine the effect of collection and storage conditions for PBMCs enriched from whole blood prior to downstream processing using our scRNAseq workflow. PBMCs were freshly isolated from whole blood collected in EDTA tubes or following storage at various timepoints and temperatures until PBMC isolation. Samples were then cryopreserved after the conclusion of each isolation stage and later processed to assess impact of cryopreservation. All PBMC samples were processed using the Chromium Single Cell Immune Profiling kit to compare gene expression and immune repertoire profiling across all storage conditions. Results: We found that gene expression data were highly correlated across all storage conditions tested. We also found that the clustering and annotation of PBMC libraries were comparable across all conditions tested, but certain subsets were more sensitive to these conditions, indicated by an elevation in cell stress and apoptosis markers. Conclusions: When planning future studies, it is imperative to consider collection and storage conditions in the workflow of processing for enabling high quality samples for single cell analysis, especially with regard to sensitive and rare cell types of interest. Citation Format: Priya J. Halvorsen, Caitlin W. Britton, Hiba Shaban, Fernando Torres, Douglas Wilson, Joseph Modarelli. Sample management for enabling successful single-cell RNAseq processing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5782.
Abstract LB562: L1-ATP8B1 exacerbated pathogenic high-level reduction-oxidation homeostasis to promote carcinogenesis in lung squamous cell carcinoma via affecting mitochondrial prohibitin 1 SUMOylation and increasing SLC1A5 expression
Authors: Jinpu Yu, Xiao Zhang, Rui Zhang, Zeguo Sun, Weijia Zhang
Journal: Cancer Research (2022)

Abstract Long Interspersed Nuclear Element-1 (LINE-1, L1) plays important roles in carcinogenesis by forming L1 chimeric transcripts (LCTs) in somatic cells. However, the regulation and function of LCTs in lung squamous cell carcinoma (LUSC) remains unclear. Previously we identified L1-ATP8B1 as a prognostic LCT in LUSC. In this study we confirmed that L1-ATP8B1 was overexpressed in LUSC patients suffering from shorter survival and correlated with upregulation of LINE-1 ORF1, impaired expression of ATPase phospholipid transporting 8B1 (ATP8B1) and distinct mitochondria dysfunction in both TCGA dataset and TJMUCH cohort. Over-expression of L1-ATP8B1 in LUSC cell lines and xenograft-bearing mice promoted cell proliferation, migration and invasion in vitro and facilitated LUSC xenografts growth in vivo which could be attenuated by inhibiting LINE-1 activity via nevirapine (NVR). In addition, L1-ATP8B1 affected cardiolipin-dependent mitochondrial prohibitin 1 (PHB1) SUMOylation and increased GSH synthesis transporter protein SLC1A5 expression which produced excessive ROS and GSH to induce cellular high-level reduction-oxidation (REDOX) homeostasis. Interfering with REDOX homeostasis using antioxidant could inhibit L1-ATP8B1 overexpression, reverse L1-ATP8B1-related mitochondrial dysfunction and carcinogenesis. Furthermore, combined therapy of NVR and antioxidant dramatically abolished L1-ATP8B1-induced growth and metastasis of LUSC xenografts in vivo. In conclusion, we at the first time demonstrated metabolic disorder plays a vital role in LCTs-related carcinogenesis and L1-ATP8B1 promotes LUSC development and progression by exacerbating pathogenic high-level REDOX homeostasis, therefore L1-ATP8B1 is a promising prognostic biomarker and therapeutic target in LUSC. Citation Format: Jinpu Yu, Xiao Zhang, Rui Zhang, Zeguo Sun, Weijia Zhang. L1-ATP8B1 exacerbated pathogenic high-level reduction-oxidation homeostasis to promote carcinogenesis in lung squamous cell carcinoma via affecting mitochondrial prohibitin 1 SUMOylation and increasing SLC1A5 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB562.